The incidence of HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC) has rapidly increased over the last two decades surpassing uterine cervical cancer as the most frequently diagnosed HPV-associated cancer in the United States by 2012. This ?epidemic? is expected to continue through 2060. Patients are typically diagnosed with metastatic nodal disease treated with high dose radiation with concurrent cisplatin. This treatment was not designed for HPV+ OPSCC but was based on results of trials of therapeutic escalation for HPV-negative cancers. This aggressive treatment results in lifelong morbidity, and side effects of therapy may also shorten lifespan. For the approximately 25% of these patients who will recur, late identification of recurrence limits salvage options for a portion. Early detection of initial disease and recurrences would allow less morbid therapy that may also increase survival. The head and neck oncology community has recently focused on personalization of therapy for HPV+ OPSCC, in particular on therapeutic de-intensification. The major stumbling block that is preventing widespread adoption of these therapeutic strategies is inability to identify patients at low risk of recurrence who are appropriate for less intensive therapy. Our group identified and piloted prognostic biomarkers and an assay for detection of treatment response and for early detection of initial or recurrent HPV+ OPSCC. The prognostic biomarker is based on deletion or mutations of TRAF3 or CYLD in tumors. Analysis of the TCGA cohort revealed that survival of HPV+ OPSCC patients with TRAF or CYLD defects was significantly better than those whose tumors lacked defects. Remarkably, HPV+ OPSCC tumors lacking TRAF3 or CYLD defects had survival that was indistinguishable from HPV-negative patients, suggesting that the improved survival in HPV+ OPSCC is largely attributable to the subset with these mutations. We also have piloted detection of circulating HPVDNA using ultrasensitive digital PCR as a measure of treatment response, predictor of recurrence, and for early detection of recurrent disease. These assays that we piloted for prognostication, as well as treatment response and early detection of initial or recurrent HPV+ OPSCC require validation before they will be clinically useful. Here we propose to partner with MD Anderson Cancer Center to leverage an ongoing trial and use detection of circulating HPVDNA to distinguish patients with oral HPV infection from those with early HPV+ OPSCC. We will also conduct a prospective observational clinical trial to validate TRAF3 and CYLD mutations as prognostic biomarkers and validate detection of circulating plasma HPVDNA for early detection of recurrent HPV+ OPSCC. Validation of prognostic biomarkers will aid appropriate selection of HPV+ OPSCC patients for de-intensified therapy while also identifying those who need aggressive or novel therapies to improve survival. Validation of a tool for prediction of response and early detection of recurrence will also change practice by identifying patients who are at increased risk of recurrence for heightened surveillance or early intervention.